Polyethylene oxide and polyisobutylene copolymers and their usage on medical devices

ABSTRACT

An implantable medical device includes a device body at least partially formed of a polymeric material including a base polymer and a block copolymer. The block copolymer includes at least one polyethylene oxide (PEO) block and at least one polyisobutylene (PIB) block. The PEO and PIB blocks may be coupled together by a urethane or urea linkage. The block copolymer may be a triblock copolymer, PEO-PIB-PEO, and the base polymer may be a polystyrene-polyisobutylene-polystyrene triblock copolymer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of copending U.S. patentapplication: 1) Ser. No. 11/281,297, filed on Nov. 16, 2005; and 2) Ser.No. 11/281,778, filed on Nov. 16, 2005, the entire disclosures of whichare incorporated herein by reference. This application shares commonsubject matter with copending U.S. patent application Ser. No.11/563,593, filed currently herewith, titled “Polyethylene Oxide andSilicone Copolymers and their Usage on Medical Devices”, which isincorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates generally to biocompatible and lubriciouscoatings, and more particularly, to polyethylene oxide andpolyisobutylene copolymers and their usage.

BACKGROUND OF THE INVENTION

Many methods and materials have been explored to achievebiocompatibility of implantable medical devices (IMD). Implantablemedical devices, as used herein, include any blood-contacting medicaldevice that is implanted in the body, chronically or otherwise,including, but not limited to, blood-contacting surgical tools,implantable cardiac devices, implantable monitors, biological sensors,implantable drug delivery devices, catheters, artificial blood vesselsand stents. For IMDs, it is especially desirable that there be minimalfriction during implant to facilitate implant dynamics. To this end,IMDs have been coated with materials which increase wet lubricity,thereby reducing procedure time, insertion forces and patientdiscomfort. Lubricity also reduces tissue irritation and damage andprovides greater control and maneuverability of the device duringimplant. Wet lubricity for hydrophobic surfaces may be achieved usinghydrophilic coatings. Such coatings also improve biocompatibility by,for example, reducing protein adsorption and platelet adhesion and otherblood interactions, as well as resisting bacterial adhesion.

For example, lead insulation materials have been surface-coated with aUV-cured polyvinylpyrrolidone (PVP) from SurModics, Inc. of EastPrairie, Minn., using PHOTOLINK® chemistry coating technique to achievethe benefits of wet lubricity and hydrophilic coatings. This coatingtechnique involves photochemical covalent bonding of the coatingmolecules to the insulation material substrate and requires severalsteps, including lead cleaning, PVP solution preparation, plasmatreatment, lead coating, photo activation and cleaning. This process iscomplex and difficult to control and can lead to poor quality coatings.

Lubricious surfaces can also be prepared by chemical grafting techniquesusing other hydrophilic materials, such as polyethylene oxide (PEO),referred to also as polyethylene glycol (PEG), which can be grafted tothe polymer substrate either as end segments or branches to the backbone of the polymer. The existing techniques and materials, however, donot provide an effective lubricious surface on a medical devices formedof a material which includes a polystyrene-polyisobutylene-polystyrenetriblock copolymer (PSIBS). A polystyrene-polyisobutylene-polystyrenetriblock copolymer may be employed as an insulation material on medicalleads.

What are needed, therefore, are new materials to achieve highlylubricious coatings for implantable medical devices, which areparticularly useful for preparing lubricious coatings on PSIBS insulatedleads or other PSIBS or polyisobutylene-based polymer parts of medicaldevices. The present invention provides PEO and polyisobutylene (PIB)copolymers to satisfy these and other needs, and provides furtherrelated advantages, as will be made apparent by the description of theembodiments that follow.

SUMMARY

Block copolymers presented herein include at least one polyethyleneoxide (PEO) block and at least one polyisobutylene (PIB) block. In oneembodiment, the block copolymer includes two polyethylene oxide (PEO)blocks and one polyisobutylene (PIB) block and is represented by theformula PEO-DI-(PIB-DI)_(n)-PEO. In this embodiment, the blockcopolymer, which is made by reacting two moles of a mono-functionalgroup terminated polyethylene oxide (mPEO) with one mole of anisocyanate-terminated prepolymer. The isocyanate-terminated prepolymeris obtained by reacting n+1 moles of diisocyanate with n moles ofdi-reactive group terminated polyisobutylene (diPIB), where n is aninteger greater than zero. DI represents a linkage between PIB and PEOblocks, and between PIB segments of a PIB block when n is greater thanone, resulting from using diisocyanate as a coupling agent. Reacting anisocyanate group of the prepolymer with the functional group of mPEOresults in a linkage (DI) between PIB and PEO blocks. DI is also aproduct or residue resulting from reaction of both isocyanate groups ofthe diisocyanate with the reactive groups of diPIB so as to couplemultiple PIB segments together.

Also presented is an implantable medical device which includes a devicebody at least partially formed of a polymeric material including a basepolymer and the block copolymer. In one embodiment, the block copolymeris one represented by the formula PEO-DI-(PIB-DI)_(n)-PEO. In anotherembodiment, the block copolymer includes at least one PEO block and atleast one PIB block and the base polymer is apolystyrene-polyisobutylene-polystyrene triblock copolymer. In anotherembodiment, the medical device is an implantable lead, where the blockcopolymer is a PEO/PIB block copolymer in which the PEO and PIB blocksare coupled together by a urethane or urea linkage.

Block copolymers that include at least one polyethylene oxide (PEO)block and at least one silicone (SI) block are also presented herein. Inone embodiment, the weight average molecular weight of the PEO/SI blockcopolymer is in the range of about 400 to about 50,000. Also presentedis an implantable medical device which includes a device body at leastpartially formed of a polymeric material including a base polymer andthe PEO/SI block copolymer. The weight average molecular weight of thePEO/SI block copolymer is in the range of about 400 to about 50,000.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The accompanying drawings, which are incorporated herein and form partof the specification, illustrate the present invention and, togetherwith the description, further serve to explain the principles of theinvention and to enable a person skilled in the relevant art(s) to makeand use the invention. In the drawings, like reference numbers indicateidentical or functionally similar elements.

FIG. 1 is a flowchart schematic illustrating a surface modificationamphiphilic copolymer (SMAC) blended into a base polymer and forming alubricious surface coating in accordance with a method disclosed herein.

FIG. 2A shows an implantable medical lead in accordance with anembodiment.

FIG. 2B is an axial cross section of a portion of the lead of FIG. 2Ahaving a lead insulation tubing formed of a blended polymeric materialin accordance with another embodiment.

FIG. 3 is an axial cross section of a portion of the lead of FIG. 2Ahaving a lead body formed of an inner base polymer layer and an outerSMAC layer in accordance with another embodiment.

DETAILED DESCRIPTION OF THE INVENTION

The following detailed description of the present invention refers tothe accompanying drawings that illustrate exemplary embodimentsconsistent with this invention. Other embodiments are possible, andmodifications may be made to the embodiments within the spirit and scopeof the present invention. Therefore, the following detailed descriptionis not meant to limit the invention. Rather, the scope of the inventionis defined by the appended claims. Thus, the operation and behavior ofthe present invention will be described with the understanding thatmodifications and variations of the embodiments are possible, given thelevel of detail presented herein.

Surface modification amphiphilic copolymers (SMAC) contain one or morehydrophilic segments and one or more hydrophobic segments. Sincehydrophilic segments of an SMAC can provide wet lubricity to a surface,SMACs can be used as to prepare lubricious coatings on medical devicebodies formed of hydrophobic base materials. Such hydrophilic segmentsmay include, for example, polyethylene oxide (PEO) (also known aspolyethylene glycol (PEG)), poly(vinyl alcohol) (PVA), polyacrylamides(PA), polyvinylpyrrolidone (PVP), and poly(hydroxyethyl methacrylate)(PHEMA). In addition, hydrophobic segments of an SMAC coating interactwith a hydrophobic base material to help anchor the SMAC coating to thesurface of the medical device. Such hydrophobic segments may include,for example, polypropylene oxide (PPO), polyurethane (PU), polystyrene(PS), polypropylene (PP), polytetrafluoroethylene (PTFE),polytetramethylene oxide (PTMO), polyisobutylene (PIB), and polyalkylsiloxane (PAS). Polyalkyl siloxane includes poly(dialkyl siloxane) suchas poly(dimethyl or diethyl siloxane). A polyalkyl siloxane segment issimply referred to herein as a silicone (SI) segment.

FIG. 1 shows a surface modification amphiphilic copolymer (SMAC) 101blended into a base polymer 102 and forming a lubricious coating 104 inaccordance with a method disclosed herein. In a blending step 110, SMAC101 is blended as an additive with a base polymer 102, producing ablended polymeric material. For example, the weight percent of SMAC 101in the blended polymeric material based on weight of base polymer may bein a range of about 0.2 percent to about 40 percent. In one embodiment,the weight percent of SMAC 101 is about five percent. In any case, theamount of SMAC 101 added to base polymer 102 should be measured so as toachieve a desired wet lubricity and its benefits such as reduction inprotein adsorption, bacteria and cell adhesion, and thrombosisformation.

As noted above, SMAC 101 includes at least one hydrophilic segment 101Aand at least one hydrophobic segment 101B. The schematic of SMAC 101 inFIG. 1 includes two hydrophilic segments 101A and one hydrophobicsegment 101B in the form of an ABA triblock copolymer, but it should beunderstood that other forms of SMAC 101 are possible, including randomblock copolymers. For example, SMAC 101 may be a block copolymer in theform of A(BA)_(n), (AB)_(n), or B(AB)_(n), wherein A is one or morehydrophilic segments 101A and B is one or more hydrophobic segments 101Band n is an integer greater than zero. For SMAC 101 in the form of ABAand BAB, the Mw of the SMAC 101 may be in the range of about 400 toabout 30,000. In one embodiment, the Mw for the SMAC 101 is in the rangeof 1,000 to 10,000. Moreover, SMAC 101 may be a random block copolymer,represented generally as a copolymer in the form of “ABBAABABA,” whereineach A and B segment may contain many monomer repeat units rather justone monomer repeat unit. It should be understood that other random formsfor a random multi-block copolymer are within the scope of the presentinvention, and “ABBAABABA” as used herein represents any randommulti-block copolymer. Moreover, each A segment and each B segment ofSMAC 101 need not be identical in kind or segment chain length to anyother A segment or B segment, respectively.

In a forming step 120, at least a part 103 of a medical device is formedwith the blended polymeric material. As schematically shown by devicepart 103A, SMAC 101 spontaneously migrates from bulk 106 to surface 108of device part 103 formed of the blended polymeric material since SMAC101 is surface active. Step 130 includes implanting the medical devicehaving device part 103 in a patient and allowing SMAC 101 to formlubricious coating 104 on device part 103, which is schematically shownin FIG. 1 as device part 103B. Hydrophilic segments 101A extend intobiological media once contacting with blood and provide device part 103with wet lubricity. Where base polymer 102 is hydrophobic, hydrophobicsegment 101B interacts with hydrophobic base polymer 102 to help anchorSMAC 101 to surface 108. Although covalent bonds between base polymer102 and SMAC 101 are not present, other chemical and physicalinteractions help entangle hydrophobic segment 101B with base polymer102 so as to anchor SMAC 101 to surface 108, especially when segment101B and polymer 102 are selected so as to have similar chemical groups,structures and/or properties.

Device part 103 formed of the blended polymeric material may include anymedical part, such as, for example, an intra-aortic balloon or a casingat least partially enclosing the medical device. For example, themedical device may be an implantable lead and device part 103 mayinclude lead insulation tubing. In such a case, a lead insulationmaterial may be used as base polymer 102. Lead insulation materialsinclude, for example, silicone rubber, silicone polyurethane copolymer(SPC), and polyurethane, such as Pellethane 2363 55D. Apolystyrene-polyisobutylene-polystyrene triblock copolymer (PSIBS) orother polyisobutylene-based copolymer (e.g., an ABA copolymer in theform X-PIB-X, X being a polymer segment other than PIB) may also be usedas base polymer 102. PSIBS may be specifically useful as lead insulationmaterial or to form other medical device parts, since it is highlyflexible, and may be more resistant to abrasion and cyclic compressionthan silicone, and more biostable than Pellethane 55D. PSIBS may beprepared using terminally functional polyisobutylene as an intermediate,and attaching polystyrene segments to each end of the polyisobutylenesegment, as should be understood to one skilled in the art. Terminallyfunctional polyisobutylenes are disclosed in U.S. Pat. Nos. 4,316,973and 4,342,849 to Kennedy, the entire disclosures of which are herebyincorporated by reference. Methods to produce PIB-based copolymers aredescribed in U.S. Pat. No. 4,910,321 to Kennedy et al., the entiredisclosure of which is hereby incorporated by reference. For example, aPSIBS copolymer may be constructed as disclosed in U.S. Pat. No.4,276,394 to Kennedy et al., the entire disclosure of which is herebyincorporated by reference.

In one embodiment of a method disclosed herein, blending step 110includes melting together SMAC 101 and base polymer 102 in an extruderto produce the blended polymeric material. For example, after basepolymer 102 is synthesized, a twin-screw extruder may be used to blendSMAC 101 with base polymer 102. The blended polymeric material may thenbe pelletized and sent for further processing for forming into devicepart 103 or may be extruded directly so as to form device part 103.

Alternatively, blending step 110 includes adding SMAC 101 into basepolymer 102 during the synthesis of base polymer 102, in which case atwin-screw extruder is not required to mix SMAC 101 and base polymer 102together. For example, SMAC 101 can be added into a reactant during thesynthesis of base polymer. In this case, the synthesized base polymer102 contains SMAC 101, and a twin-screw extruder is not required to mixSMAC 101 and base polymer 102 together. In step 120, an extrusionmethod, for example, may be employed to construct device part 103 formedof the blended polymeric material.

An implantable medical device having device part 103 formed of theblended polymeric material will now be described. In one embodiment, themedical device includes a device body and a casing formed of the blendedpolymeric material which at least partially encloses the device body.The blended polymeric material may include base polymer 101 and any oneor combination of the SMACs 101, including the PEO/SI or the PEO/PIBblock copolymers further described below. FIG. 2A illustrates animplantable medical device in the form of a body implantable lead 200.Lead 200 includes a device body 212 having a proximal end portion 216and a distal end portion 214, which includes a tip electrode 227, ashocking electrode 228, and a sensing electrode 229. The proximal endportion 216 includes a bifurcated connector assembly 226 coupling thelead 200 to a pacemaker/defibrillator.

The lead body 212 includes a casing 222 formed of the blended polymericmaterial. In one embodiment, casing 222 forms an insulative tubingenclosing a coil conductor 240, as illustrated in FIG. 2B. In FIG. 2A,casing 222 extends along substantially the entire length of lead body212. As noted above, the blended polymeric material forming casing 222includes an SMAC blended with a base polymer, and therefore a lubriciouscoating forms on the casing when lead 200 is implanted, which improvesbiocompatibilities by decreasing protein adsorption, bacteria and celladhesion, and thrombosis formation. Where casing 222 forms an insulativetubing, the base polymer in the blended polymeric material can be a leadinsulation material, such as, for example, silicone rubber,polyurethane, silicone polyurethane copolymer (SPC), PSIBS or othersuitable polyisobutylene-based copolymer.

Specific SMACs 101 will now be described. In one embodiment, a specificSMAC 101 includes at least one PEO block and at least one silicone (SI)block wherein the weight average molecular weight (M_(w)) of thisparticular SMAC is in the range of about 400 to about 50,000. ThisPEO/SI block copolymer may be in the form of ABA, BAB, AB, for example,and may also be a random multi-block copolymer, represented generally asa copolymer in the form of ABBAABABA, as defined above. For this PEO/SIblock copolymer, whether in the form of ABA, as illustrated in FIG. 1,or BAB or AB, and so on, each block A includes one or more hydrophilicsegments of PEO (101A) and each block B includes one or more hydrophobicsegments of SI (101B). For the PEO/SI block copolymer in the form of ABAand BAB, the M_(w) of the block copolymer may be in the range of about400 to about 30,000. In one embodiment, the M_(w) of the PEO/SI blockcopolymer is in the range of 1,000 to 10,000. In one embodiment wherethe PEO/SI block copolymer is a random multi-block copolymer describedabove (ABBAABABA), the M_(w) of the block copolymer may be in the rangeof about 5000 to about 50,000. In one embodiment, the M_(w) of eachblock A of PEO is in the range of about 150 to about 15,000, and inanother embodiment the M_(w) of each block B of SI is in the range ofabout 200 to about 15,000, whether the PEO/SI block copolymer is theform of ABA, BAB, AB or a random block copolymer. The chain lengths ofsegment(s) in a block A (or in a block B) may be the same or differentwithin the same block, and the same or different with respect to thesegment(s) of another block A (or another block B) if the PEO/SI blockcopolymer contains more than one block A (or more than one block B).

In one embodiment, when multiple segments of PEO in a block A and/ormultiple segments of SI in a block B are present, the segments withinthe block are connected together using isocyanate chemistry. Isocyanatechemistry may also be used to couple a block A and a block B together.In one embodiment, the PEO/SI block copolymer in the form of ABA maycontain one SI segment or multiple SI segments connected together by alinkage DI. As shall be further described below, DI represents thelinkage which is produced by reacting each of the isocyanate groups of adiisocyanate with a reactive/functional group from a PEO or SI segment.Each functional group may be an hydroxyl or amine group, for example. Insuch a case, DI may include a urethane or urea linkage having twourethane or urea functional groups between coupled segments or blocks.

As is well known in the art, a diisocyanate can be employed as a linkingor coupling agent via the following chemistry shown in Scheme 1.

For example, in the case of cyclohexyl diisocyanate, Y would be

For a PEO/SI block copolymer in the form of ABA, a block B may include nSI segments connected together by DI. In such a case, n moles ofdi-reactive group terminated silicone (diSI) molecules may be reactedwith n+1 moles of a diisocyanate, where n is an integer greater thanzero, thereby forming n segments connected together. The combinedsegments are terminated on the ends by an isocyanate group to form anisocyanate-terminated prepolymer to later allow coupling of block B toblocks A, as further described below. The diisocyanate may include, forexample, methylene bis-(4-phenyl isocyanate) (MDI), hexamethylenediisocyanate (HMDI), methylene bis (p-cyclohexyl isocyanate) (H12MDI),3,3-bi-toluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), ortoluene diisocyanate (TDI). For the DI connecting SI segments together,the DI is a product of reacting the diisocyanate with the reactivegroups of diSI. DI will include a urethane or urea linkage when thereactive groups of diSI are hydroxyl or amine groups, respectively. Theresulting urethane or urea linkage between coupled SI segments mayinclude two urethane or urea functional groups (with an organic residuein between) resulting from reacting the two isocyanate groups of thediisocyanate. DI may also be the linkage coupling SI and PEO segmentstogether, when isocyanate groups are used as a coupling agent, asfurther described below. In such an instance, the PEO/SI block copolymeris represented by the formula PEO-DI-(SI-DI)_(n)-PEO. Hence, where n isgreater than one, a PEO/SI block copolymer in the form of ABA includesmultiple SI segments linked together to form block B.

Exemplary methods for making the PEO/SI block copolymer of various formswill now be described. For synthesis of PEO-DI-(SI-DI)_(n)-PEO, atwo-stage method may be employed. Firstly, as described above, n+1 molesof a diisocyanate is reacted with n moles diSI to obtain anisocyanate-terminated prepolymer (i.e., SI terminated on each end withan isocyanate group). Secondly, two moles of mono-functional groupterminated polyethylene oxide (mPEO) are reacted with one mole of theisocyanate-terminated prepolymer. An exemplary diSI may be a SI moleculeterminated on each end by a reactive group such as a hydroxyl or anamine group. An exemplary mPEO may be a PEO molecule terminated on oneend by a functional group such as a hydroxyl or amine group. In such acase, DI may be a urethane or urea linkage having two urethane or ureafunctional groups between coupled blocks of PEO and SI. The other end ofthe PEO molecule may be terminated by a suitable alkoxy group, such asmethoxy or ethoxy, for example. Accordingly, a specific mPEO may be amonomethoxy, monohydroxyl-terminated PEO.

A similar two-stage synthesis method may be used for making the PEO/SIblock copolymer in the form BAB represented by the formulaSI-DI-(PEO-DI)_(n)-SI, wherein n is an integer greater than zero, suchthat block A has one or more segments of PEO. Accordingly, the block Amay be one PEO segment or multiple PEO segments connected together byDI. Using the two-stage method described above, SI-DI-(PEO-DI)_(n)-SI isformed by firstly reacting n+1 moles of a diisocyanate with n moles ofdi-reactive PEO (diPEO) to obtain an isocyanate-terminated prepolymer,and secondly reacting two moles of mono-functional group terminated SI(mSI) (e.g., monomethoxy, monohydroxy-terminated SI) with one mole ofthe isocyanate-terminated prepolymer. The diPEO is terminated on eachend by a reactive group such as a hydroxyl or amine group. The mSI isterminated by a functional group such as a hydroxyl or amine group onone end of the mSI molecule. For mPEO, mSI, diPEO, and diSI, it shouldbe understood that other reactive groups can also be used to react withisocyanates to prepare the PEO/SI block copolymers.

The exemplary two-stage method discussed above may also be used formaking the PEO/SI block copolymer in the form AB represented by theformula PEO-DI-SI. In this case, one mole of diisocyanate is reactedwith one mole of mSI to obtain a monoisocyanate-terminated prepolymer,and one mole of mPEO is reacted with one mole of themonoisocyanate-terminated prepolymer.

For synthesis of a random multi-block copolymer represented by theformula PEO-DI-SI-DI-SI-DI-PEO-DI-PEO-DI-SI-DI-PEO-DI-SI-DI-PEO, theexemplary two-stage method includes (1) reacting n+1 moles ofdiisocyanate with m moles of diSI and n−m moles of diPEO to obtain amulti-block isocyanate-terminated prepolymer, wherein n and m areintegers greater than zero, and (2) reacting two moles of mPEO with onemole of the isocyanate-terminated prepolymer.

Another specific SMAC 101 presented herein includes at least one PEOblock and at least one polyisobutylene (PIB) block. This PEO/PIB blockcopolymer may be in the form of ABA, BAB, AB, for example, and may alsobe a random multi-block copolymer, represented generally as a copolymerin the form of ABBAABABA, as defined above. For this PEO/PIB blockcopolymer, whether in the form of ABA, as illustrated in FIG. 1, or BABor AB, and so on, each block A includes one or more hydrophilic segmentsof PEO (101A) and each block B includes one or more hydrophobic segmentsof PIB (101B). For the PEO/PIB block copolymer in the form of ABA andBAB, the M_(w) of the block copolymer may be in the range of about 400to about 60,000. In one embodiment where the PEO/PIB block copolymer isa random multi-block copolymer described above, the M_(w) of the PEO/PIBblock copolymer may be in the range of about 5000 to about 60,000. Inone embodiment, the M_(w) of each block A of PEO is in the range ofabout 150 to about 20,000, and in another embodiment the M_(w) of eachblock B of PIB is in the range of about 200 to about 30,000, whether thePEO/PIB block copolymer is the form of ABA, BAB, AB or a random blockcopolymer. A single segment of PIB of block B may have M_(w) in therange of about 200 to about 20,000. The chain lengths of segment(s) in ablock A (or in a block B) may be the same or different within the sameblock, and the same or different with respect to the segment(s) ofanother block A (or another block B) if the PEO/PIB block copolymercontains more than one block A (or more than one block B).

In one embodiment, when multiple segments of PEO in a block A and/ormultiple segments of PIB in a block B are present, Di is the linkagebetween the segments of a block, as well as between the blocks A and/orB. Such a final product may be obtained using a two-stage synthesismethod similar to that described above for the PEO/SI block copolymers.For a PEO/PIB block copolymer in the form of ABA, a block B may includen PIB segments connected together by DI. In such a case, n moles ofdi-reactive group terminated polyisobutylene (diPIB) molecules may bereacted with n+1 moles of a diisocyanate, where n is an integer greaterthan zero, thereby forming n PIB segments connected together. The DI isa product of reacting the diisocyanate with the reactive groups ofdiPIB. DI may be a urethane or urea linkage when the reactive groups ofdiPIB are hydroxyl or amine groups, respectively. The resulting urethaneor urea linkage between coupled PIB segments may include two urethane orurea functional groups resulting from reacting the two isocyanate groupsof the diisocyanate. The combined segments are terminated on the ends byan isocyanate group to form an isocyanate-terminated prepolymer to laterallow coupling of block B to blocks A, as further described below. Thus,DI may also be the linkage coupling PIB and PEO segments together, whenisocyanate groups are used as a coupling agent, as further describedbelow. In such an instance, the PEO/PIB block copolymer is representedby the formula PEO-DI-(PIB-DI)_(n)-PEO. Hence, where n is greater thanone, a PEO/PIB block copolymer in the form of ABA includes multiple PIBsegments linked together to form block B.

For synthesis of PEO-DI-(PIB-DI)_(n)-PEO, a two-stage method may beemployed. Firstly, as described above, n+1 moles of a diisocyanate isreacted with n moles diPIB to obtain an isocyanate-terminated prepolymer(i.e., PIB terminated on each end with an isocyanate group). Secondly,two moles of mono-functional group terminated polyethylene oxide (mPEO)are reacted with one mole of the isocyanate-terminated prepolymer. Anexemplary diPIB may be a PIB molecule terminated on each end by areactive group such as a hydroxyl or an amine group. An exemplary mPEOmay be a PEO molecule terminated on one end by a functional group suchas a hydroxyl or amine group. In such a case, DI may be a urethane orurea linkage having two urethane or urea functional groups betweencoupled blocks of PEO and PIB. The other end of the PEO molecule may beterminated by a suitable alkoxy group, such as methoxy or ethoxy, forexample. Accordingly, a specific mPEO may be a monomethoxy,monohydroxyl-terminated PEO.

A similar synthesis two-stage method may be used for making the PEO/PIBblock copolymer in the form BAB represented by the formulaPIB-DI-(PEO-DI)_(n)-PIB, wherein n is an integer greater than zero, suchthat block A has one or more segments of PEO. Accordingly, the block Amay be one PEO segment or multiple PEO segments connected together byDI. Using the two-stage method described above, PIB-DI-(PEO-DI)_(n)-PIBis formed by firstly reacting n+1 moles of a diisocyanate with n molesof di-reactive PEO (diPEO) to obtain an isocyanate-terminatedprepolymer, and secondly reacting two moles of mono-functional groupterminated PIB (mPIB) (e.g., monomethoxy, monohydroxy-terminated PIB)with one mole of the isocyanate-terminated prepolymer. The diPEO isterminated on each end by a reactive group such as a hydroxyl or aminegroup. The mPIB is terminated by a functional group such as a hydroxylor amine group on one end of the mPIB molecule. For mPEO, mPIB, diPEO,and diPIB, it should be understood that other reactive groups can alsobe used to react with isocyanates to prepare the PEO/PIB blockcopolymers.

The exemplary two-stage method discussed above may also be used formaking the PEO/PIB block copolymer in the form AB represented by theformula PEO-DI-PIB. In this case, one mole of diisocyanate is reactedwith one mole of mPIB to obtain a monoisocyanate-terminated prepolymer,and one mole of mPEO is reacted with one mole of themonoisocyanate-terminated prepolymer.

For synthesis of a random multi-block copolymer represented by theformula PEO-DI-PIB-DI-PIB-DI-PEO-DI-PEO-DI-PIB-DI-PEO-DI-PIB-DI-PEO, theexemplary two-stage method includes (1) reacting n+1 moles ofdiisocyanate with m moles of diPIB and n−m moles of diPEO to obtain amulti-block isocyanate-terminated prepolymer, wherein n and m areintegers greater than zero, and (2) reacting two moles of mPEO with onemole of the isocyanate-terminated prepolymer.

SMACs are particularly advantageous when hydrophobic block B of SMAC 101has a chemical structure similar to base polymer 102, becauseinteractions between the hydrophobic block B and a hydrophobic matrix ofbase polymer 102 help to anchor lubricious coating 104 to surface 108.The interactions may involve chain entanglements and various otherphysical interactions. For example, with reference to the schematic ofFIG. 1, where a PEO/PIB block copolymer, such as PEO-PIB-PEO, is used asSMAC 101, and PSIBS, or other polyisobutylene-based copolymer, is usedas base polymer 102, strong interactions between hydrophobic basepolymer 102 having a PIB block and the hydrophobic PIB segment(s) (101B)of the PEO/PIB block copolymer help to anchor lubricious coating 104 tosurface 108. Where a PEO/SI block copolymer, such as PEO-SI-PEO, is usedas SMAC 101, and silicone rubber or a silicone polyurethane copolymer,for example, is used as base polymer 102, strong interactions between asilicone matrix of base polymer 102 and silicone block (101B) of thePEO/SI block copolymer help to anchor lubricious coating 104 to surface108.

The PEO/SI or PEO/PIB block copolymers described herein are SMACs whichmay be employed in the methods outlined above for providing a lubriciouscoating on a medical device. For example, a PEO/SI or PEO/PIB blockcopolymer may be blended with the base polymer as an additive, either byadding to a reactant during synthesis of base polymer 102 or by meltingthe block copolymer and the base polymer together in an extruder, toproduce the blended polymeric material used to form device part 103 of amedical device, such as casing 222 in FIGS. 2A and 2B described above.When the device is implanted, the block copolymer migrates to an outersurface of the device part formed of the blended polymeric materialsince the block copolymer is surface active. The PEO/SI or PEO/PIB blockcopolymers can be also used for other applications, both in and out ofthe medical field. Moreover, other methods can be employed using thePEO/SI or PEO/PIB block copolymers to prepare lubricious coatings ofsubstrates. For example solution casting, dip-coating and adsorptiontechniques further described below may be employed.

An example solution-casting method to obtain device part 103 formed ofthe blended polymeric material via solution-casting may include thesteps of mixing the PEO/SI or PEO/PIB block copolymers with base polymer102 in solution to produce a solution mixture, casting the solutionmixture, and evaporating the solvent. For example, dimethyl formamide(DMF) or other solvent may be used as a cosolvent for the blockcopolymer and the base polymer. The base polymer may be dissolved in DMFat a concentration in a range of 2-25%, such as 5%. The block copolymermay be dissolved in the polymer solution at a concentration in a rangebetween 0.2% and 40% by weight of base polymer content. Alternatively,solutions of the block copolymers and the base polymer may be preparedseparately and then mixed. To prepare a film of the blended polymericmaterial, for example, the mixed polymer solution is cast onto cleancasting dishes and the cast films are dried in a ventilation oven at 60degrees for 24 hours and then in a vacuum oven at 60 degrees for 24hours to remove the solvent. A crosslinking agent may be added to thesolution mixture to permanently prevent the block copolymer fromescaping surface 108 of device part 103. By “permanently prevent” ismeant that the crosslinking substantially entraps the PEO/SI (orPEO/PIB) block copolymer in base polymer 102 so that little or none ofthe block copolymer leaches out into contacting bodily fluids. Anexample procedure for crosslinking is described in Platelet adhesiononto segmented polyurethane film surfaces modified by addition andcrosslinking of PEO-containing block copolymers, J. H. Lee, et al.,Biomaterials 21:683-691 (2000), incorporated herein by reference in itsentirety.

An implantable medical device such as lead 200 described above withreference to FIGS. 2A and 2B may include a device body 212 at leastpartially formed of a polymeric material including a base polymer andselected block copolymers of one or more SMACs. For example, theselected block copolymers may include any one or combination of thePEO/SI block copolymers described above, or in another embodiment, anyone or combination of PEO/PIB block copolymers described above. In oneembodiment, the selected block copolymer is a PEO/SI block copolymerdescribed herein, and in another embodiment, the selected blockcopolymer is a PEO/PIB block copolymer represented by the formulaPEO-DI-(PIB-DI)_(n)-PEO, which may be made using the two-stage methoddescribed above. In another embodiment, the selected block copolymersare one or more PEO/SI block copolymers used together with one or moreother SMACs 101. In another embodiment, the selected block copolymersare one or more PEO/PIB block copolymers together with one or more otherSMACs 101.

In one embodiment, the implantable medical device is a lead, the basepolymer is a lead insulation material, such as silicone, siliconepolyurethane copolymer, polyurethane, or PSIBS or otherpolyisobutylene-based copolymer suitable for lead insulation material,and the device part formed of the polymeric material is lead insulationtubing, such as casing 222 in FIGS. 2A and 2B or a later-describeddevice body 312 illustrated in FIG. 3. The selected block copolymersform a lubricous coating on lead insulation tubing 222 or 312 when lead200 is implanted.

In another embodiment, illustrated in FIG. 3 as an axial cross-sectionof a portion of the lead of FIG. 2A, the polymeric material at leastpartially forms a device body 312 which includes an inner layer 322 aformed of the base polymer coated by an outer layer 322 b formed of theselected block copolymers. In FIG. 3, device body 312 including layers322 a and 322 b coaxially surrounds a coil conductor 340. In oneembodiment, outer layer 322 b may be deposited on inner layer 322 ausing a coating method, such as dip-coating or adsorption methods, orother methods of forming outer layer 322 b and affixing to inner layer322 a. For example, to obtain outer layer 322 b deposited on inner layer322 a by dip-coating, inner layer 322 a is immersed in a solutionmixture of the selected block copolymers and a solvent, which may bewater or an organic chemical, and the solvent is evaporated. Anadsorption method may include immersing inner layer 322 a into anaqueous solution of the selected block copolymers and allowing theselected block copolymers to be adsorbed on the surface of inner layer322 a so as to form outer layer 322 b. Adsorption occurs through thestrong hydrophobic interactions between the hydrophobic segment(s) ofthe selected block copolymers of outer layer 322 b and a hydrophobicmatrix included in the base polymer of inner layer 322 a. For example,in one embodiment, outer layer 322 b is formed of a PEO/PIB blockcopolymer, and the base polymer of inner layer 322 a includes PSIBS orother polyisobutylene-based copolymer. The PIB segment(s) of the PEO/PIBblock copolymer of outer layer 322 b interact with the PIB segment ofthe base polymer due to their similar chemical structures. These stronginteractions anchor the PEO/PIB block copolymer of outer layer 322 b tobase polymer of inner layer 322 a. In another embodiment, outer layer322 b is formed of a PEO/SI block copolymer, and the base polymer ofinner layer 322 a includes silicone or SPC. The SI segment(s) of thePEO/SI block copolymer of outer layer 322 b interact with the siliconematrix of the base polymer due to their similar chemical structures.These strong interactions anchor the PEO/SI block copolymers of outerlayer 322 b to base polymer of inner layer 322 a.

Example embodiments of the methods, systems, and components of thepresent invention have been described herein. As noted elsewhere, theseexample embodiments have been described for illustrative purposes only,and are not limiting. Other embodiments are possible and are covered bythe invention. Such embodiments will be apparent to persons skilled inthe relevant art(s) based on the teachings contained herein. Thus, thebreadth and scope of the present invention should not be limited by anyof the above-described exemplary embodiments, but should be defined onlyin accordance with the following claims and their equivalents.

1. An implantable lead comprising a lead body at least partially formed of a block copolymer comprising two polyethylene oxide (PEO) blocks and one polyisobutylene (PIB) block, the block copolymer being represented by the formula PEO-DI-(PIB-DI)_(n)-PEO, the block copolymer being made by reacting two moles of a mono-functional group terminated polyethylene oxide (mPEO) with one mole of an isocyanate-terminated prepolymer, the isocyanate-terminated prepolymer being obtained by reacting n+1 moles of a diisocyanate with n moles of di-reactive group terminated polyisobutylene (diPIB), wherein n is an integer greater than zero, wherein DI represents a linkage which is the product of reacting an isocyanate group of the prepolymer with the functional group of mPEO, and is the product of reacting both isocyanate groups of the diisocyanate with the reactive groups of diPIB so as to couple multiple PIB segments together when n is greater than one.
 2. The implantable lead of claim 1, wherein the diisocyanate is selected from a group consisting of methylene bis-(4-phenyl isocyanate) (MDI), hexamethylene diisocyanate (HMDI), methylene bis (p-cyclohexyl isocyanate) (H₁₂MDI), 3,3-bi-toluene diisocyanate (TODI), cyclohexyl diisocyanate (CHDI), or toluene diisocyanate (TDI).
 3. The implantable lead of claim 1, wherein the DI includes a urea or urethane linkage resulting from reaction of a isocyanate group with (a) a functional group of mPEO that is a hydroxyl or an amine group, or (b) a functional group of diPIB that is a hydroxyl or an amine group.
 4. The implantable lead of claim 1, wherein the weight average molecular weight of the block copolymer is in the range of about 400 to about 60,000.
 5. An implantable medical device, comprising a device body at least partially formed of a polymeric material including a base polymer and a block copolymer, the block copolymer being represented by the formula PEO-DI-(PIB-DI)_(n)-PEO, the block copolymer being made by reacting two moles of a mono-functional group terminated polyethylene oxide (mPEO) with one mole of an isocyanate-terminated prepolymer, the isocyanate-terminated prepolymer being obtained by reacting n+1 moles of a diisocyanate with n moles of di-reactive group terminated polyisobutylene (diPIB), wherein n is an integer greater than zero, wherein DI represents a linkage which is the product of reacting an isocyanate group of the prepolymer with the functional group of mPEO, and is the product of reacting both isocyanate groups of the diisocyanate with the reactive groups of diPIB so as to couple multiple PIB segments together when n is greater than one, and wherein the implantable medical device is a lead, the base polymer is a lead insulation material, and the device body formed of the polymeric material includes a lead insulation tubing.
 6. The implantable medical device of claim 5, wherein the lead insulation material is a polystyrene-polyisobutylene-polystyrene triblock copolymer (PSIBS).
 7. An implantable lead, comprising a lead body at least partially formed of a polymeric material including a base polymer and a block copolymer, the block copolymer having at least one polyethylene oxide (PEO) block and at least one polyisobutylene (PIB) block, wherein the PEO and the PIB blocks are coupled together by a urethane or urea linkage.
 8. The implantable lead of claim 7, wherein the weight average molecular weight of the block copolymer is in the range of about 400 to about 60,000.
 9. The implantable lead of claim 7, wherein the block copolymer is in the form of ABA, BAB, AB, or a random multi-block copolymer represented generally in the form of ABBAABABA, wherein each block A is PEO and each block B is PIB.
 10. The implantable lead of claim 7, wherein the device body formed of the polymeric material includes a lead insulation tubing.
 11. The implantable lead of claim 10, wherein the block copolymer is configured to form a lubricious coating on the lead insulation tubing when the lead is implanted.
 12. The implantable lead of claim 11, wherein the lubricious coating is configured to improve biocompatibilities by decreasing protein adsorption, bacteria and cell adhesion, and thrombosis formation.
 13. An implantable lead, comprising a lead body at least partially formed of a polymeric material including a base polymer and a block copolymer, wherein the block copolymer has at least one polyethylene oxide (PEO) block and at least one polyisobutylene (PIB) block, wherein the base polymer is a polystyrene-polyisobutylene-polystyrene triblock copolymer (PSIBS).
 14. The implantable lead of claim 13, wherein the block copolymer is in the form of ABA wherein each block A is one or more PEO segments linked together and the block B is one or more PIB segments linked together, wherein the weight average molecular weight of the block copolymer is in the range of about 400 to about 60,000.
 15. The implantable lead of claim 14, wherein the weight average molecular weight of each block A is in the range of about 150 to about 20,000.
 16. The implantable lead of claim 14, wherein the weight average molecular weight of the block B is in the range of about 200 to about 30,000, wherein a PIB segment of the block B has a weight average molecular weight in the range of about 200 to about 20,000.
 17. The implantable lead of claim 13, wherein the PEO and the PIB blocks are coupled together by a urethane or urea linkage. 